This proposal entitled, "Phase I Clinical Trials of Anti-Cancer Agents," prepared in response to RFA No. CA-02-011, requests support for early stage clinical evaluations, particularly phase I, pharmacological and relevant biological studies, of investigational anti-cancer therapeutics. The greatest advances in the cancer therapy have resulted from the introduction of novel anti-cancer therapeutics and their subsequent optimization (i.e. dosing, scheduling, sequencing, deployment in combination) for clinical practice. The phase I stage represents a crucial step in this developmental process, and the reliability of clinical and supportive pharmacological and biological data may significantly impact on the expedient and optimal development of new therapies. This is especially true for selective rationally-designed, target-based agents. The sheer number investigational candidates is striking relative to available developmental resources, and prioritization of these resources by considering the ultimate impact of the therapeutic represent major developmental challenges that must be overcome. Furthermore, unlike nonspecific cytotoxics, in which anti-cancer activity is often dose-related and, hence, the maximum tolerated dose (MTD) is generally sought, the preponderance of preclinical data with selective target-based therapeutics suggest that maximal biological effects will occur at doses that are substantially lower than the MTD. Selection of a maximal biological dose would likely result in greater therapeutic indices and more "breathing room" for combination development. The preponderance of preclinical data also suggests that the predominant beneficial effects of target-based therapeutics will be tumor growth inhibition, which may not be appreciated in nonrandomized studies. This proposal will describe the San Antonio Drug Development Group's (SADDG) approach to meet these challenges. The specific aims are directed at discerning both traditional phase I study endpoints (e.g. MTD, characterization of toxicity) and relevant biological and pharmacological endpoints (e.g. maximally effective dose.) The latter is particularly important in view of the expectations that many novel anti-cancer agents may not have clear toxicological endpoints, and the prospects for clinical utility may not be known until further evaluations have been completed. Therefore, other specific aims, including the assessment of relevant biological activity at the target level, are of utmost importance to ultimately optimize the therapeutic indices of investigational cancer therapies. The SADDG proposes to perform rigorous and comprehensive toxicological, pharmacological, and biological evaluations in the course of early clinical trials. The results will be synthesized to address therapeutic optimization issues, ascertain proof of principle, and develop assays to discern the relevant effects of the therapy on the target. The development of such assays may be even more crucial for subsequent disease-directed studies to gauge biological targeting and/or tumor growth inhibition in vivo. In addition to the methodology proposed to meet these challenges, the proposal will demonstrate the immense experience, success, and dedication of the SADDG to the comprehensive development of anti-cancer therapeutics, as well as the strong institutional commitment.